Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure.

BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies.

AIMS: Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. METHODS AND RESULTS: A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute bioavailability of SC compared with IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment-emergent adverse events, infusion site pain, device performance, and PK measurements.The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump, there were no treatment-emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site. CONCLUSION: The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.

Incremental prognostic value of biomarkers in PARADIGM-HF.

AIMS: It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure. METHODS AND RESULTS: Aldosterone, cystatin C, high-sensitivity troponin T (hs-TnT), galectin-3, growth differentiation factor-15 (GDF-15), kidney injury molecule-1, matrix metalloproteinase-2 and -9, soluble suppression of tumourigenicity-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM-HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT-HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all-cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow-up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs-TnT, GDF-15, cystatin C and TIMP-1. When all biomarkers were added simultaneously to the PREDICT-HF models, only hs-TnT remained an independent predictor of all three endpoints. GDF-15 also remained predictive of the primary endpoint; TIMP-1 was the only other predictor of both cardiovascular and all-cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification. CONCLUSIONS: None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables.

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Reference Ranges for NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) and Risk Factors for Higher NT-proBNP Concentrations in a Large General Population Cohort.

BACKGROUND: Demographic differences in expected NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration are not well established. We aimed to establish reference ranges for NT-proBNP and explore the determinants of moderately elevated NT-proBNP under the universal definition of heart failure criteria. METHODS: This is a cross-sectional study. NT-proBNP was measured in serum from 18 356 individuals without previous cardiovascular disease in the Generation Scotland Scottish Family Health Study. Age- and sex-stratified medians and 97.5th centiles were generated. Sex stratified risk factors for moderately elevated NT-proBNP (≥125 pg/mL) were investigated. RESULTS: In males, median (97.5th centile) NT-proBNP concentration at age <30 years was 21 (104) pg/mL, rising to 38 (195) pg/ml at 50 to 59 years, and 281 (6792) pg/mL at ≥80 years. In females, median NT-proBNP at age <30 years was 51 (196) pg/mL, 66 (299) pg/mL at 50 to 59 years, and 240 (2704) pg/mL at ≥80 years. At age <30 years, 9.8% of females and 1.4% of males had elevated NT-proBNP, rising to 76.5% and 81.0%, respectively, at age ≥80 years. After adjusting for risk factors, an NT-proBNP ≥125 pg/mL was more common in females than males (OR, 9.48 [95% CI, 5.60-16.1]). Older age and smoking were more strongly associated with elevated NT-proBNP in males than in females (Psex interaction <0.001, 0.07, respectively). Diabetes was inversely associated with odds of elevated NT-proBNP in females only (Psex interaction=0.007). CONCLUSIONS: An NT-proBNP ≥125 pg/mL is common in females without classical cardiovascular risk factors as well as older people. If NT-proBNP becomes widely used for screening in the general population, interpretation of NT-proBNP levels will require that age and sex-specific thresholds are used to identify patients with potential pathophysiology.

Laryngoscopic findings of age-related vocal fold atrophy are reliable but not specific.

OBJECTIVES: We aimed to evaluate the reliability of laryngoscopic features of vocal fold atrophy as assessed by novice otolaryngology trainees and expert laryngologists. DESIGN: Two expert fellowship-trained laryngologists and three non-expert otolaryngology resident trainees were recruited to view 50 anonymised laryngo-stroboscopic examinations of patients presenting with dysphonia and non-voice, laryngeal complaints. Reviewers were asked to stratify the patient's age, provide an opinion about the presence of age-related vocal fold atrophy and specify which laryngoscopy features were present to make the diagnosis. SETTING: Tertiary care laryngology practice. PARTICIPANTS: Two fellowship-trained laryngologists and three trainee otolaryngologists. MAIN OUTCOME MEASURES: Accuracy of age categorisation was determined and Kappa analysis was performed to assess inter-rater agreement. RESULTS: The mean age of patients was 54.9 years old with near equal male to female distribution. The overall accuracy of age category determination by raters was only 30.8%. Kappa analysis demonstrated fair agreement regarding the presence of vocal fold atrophy in non-expert reviewers, and moderate agreement amongst expert reviewers. Features of glottic gap, muscular atrophy of vocal folds and prominent vocal processes were all identified with high agreement (>80.0%). CONCLUSION: Our study illustrates that while raters can agree on the presence of age-related vocal fold atrophy, the findings may be non-specific and do not necessarily correlate with age.

Feminization Laryngoplasty: 17-Year Review on Long-Term Outcomes, Safety, and Technique.

OBJECTIVES: Transfeminine patients can experience significant gender dysphoria in vocal communication. Feminization laryngoplasty (FL) is a gender-affirming surgery developed to elevate speaking vocal range, as well as alter vocal resonance and laryngeal cosmesis. The purpose here was to appraise FL's long-term voice outcomes across a 17-year review period. STUDY DESIGN: Level III, retrospective study and description of technique. SETTING: A single-institution transfeminine voice clinic. METHODS: Voice data (speaking fundamental frequency [F0], lowest F0, highest F0, F0 range in both Hertz and semitones, and maximum phonation time [MPT]) were collected and assessed. Self-assessment of voice femininity and complications were documented. RESULTS: The 162 patients, all transfeminine women, had a mean age of 40 years with 36-month mean follow-up. There were significant increases in mean speaking F0 (Δ = 50 ± 30 Hz, Δ = 6 ± 3 semitones; P < .001) and mean change in lowest F0 (Δ = 58 ± 31 Hz, Δ = 8 ± 4 semitones; P < .001). There was no significant difference in mean change in highest F0 or MPT. There was significant improvement (Δ = 60% ± 39%; P < .001) in perceptual self-assessment of vocal femininity. There was a 1.2% rate of major postoperative complications requiring inpatient admission or operative intervention. There were no differences in vocal outcomes between those patients who had less than 1-year follow-up and those who had 5-year follow-up. CONCLUSION: FL in this cohort was a safe and effective technique for increasing mean speaking F0, mean lowest F0, and voice gender perception over a prolonged follow-up period. These findings add to the possible treatments aimed at addressing the morbid dysphoria related to voice and communication for our transfeminine patients.

Low-Molecular-Weight Seaweed-Derived Polysaccharides Lead to Increased Faecal Bulk but Do Not Alter Human Gut Health Markers.

Seaweeds are potentially sustainable crops and are receiving significant interest because of their rich bioactive compound content; including fatty acids, polyphenols, carotenoids, and complex polysaccharides. However, there is little information on the in vivo effects on gut health of the polysaccharides and their low-molecular-weight derivatives. Herein, we describe the first investigation into the prebiotic potential of low-molecular-weight polysaccharides (LMWPs) derived from alginate and agar in order to validate their in vivo efficacy. We conducted a randomized; placebo-controlled trial testing the impact of alginate and agar LWMPs on faecal weight and other markers of gut health and on composition of gut microbiota. We show that these LMWPs led to significantly increased faecal bulk (20-30%). Analysis of gut microbiome composition by sequencing indicated no significant changes attributable to treatment at the phylum and family level, although FISH analysis showed an increase in Faecalibacterium prausnitzii in subjects consuming agar LMWP. Sequence analysis of gut bacteria corroborated with the FISH data, indicating that alginate and agar LWMPs do not alter human gut microbiome health markers. Crucially, our findings suggest an urgent need for robust and rigorous human in vivo testing-in particular, using refined seaweed extracts.

The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis.

In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo.

Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight.

Adverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

BACKGROUND: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. METHODS: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a ß-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. RESULTS: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. CONCLUSIONS: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Urinary peptides in heart failure: a link to molecular pathophysiology.

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P < 0.0001). No separation based on HF subtype was detectable. CONCLUSIONS: Heart failure, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.

Rationale and methods of a randomized trial evaluating the effect of neprilysin inhibition on left ventricular remodelling.

AIMS: In patients at high risk of heart failure following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse left ventricular (LV) remodelling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic, and sympatholytic effects. METHODS: We designed a randomized, double-blinded, active-comparator trial to examine the effect of sacubitril/valsartan to the current standard of care in reducing adverse LV remodelling in patients with asymptomatic LVSD following MI. Eligible patients were ≥3 months following MI, had an LV ejection fraction ≤40% as measured by echocardiography, were New York Heart Association functional classification I, tolerant of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at equivalent dose of ramipril 2.5 mg twice daily or greater, and taking a beta-blocker unless contraindicated or intolerant. Patients were randomized to sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan (target dose 160 mg twice daily). The primary endpoint will be change in LV end-systolic volume indexed for body surface area measured using cardiac magnetic resonance imaging over 52 weeks from randomization. Secondary endpoints include other magnetic resonance imaging-based metrics of LV remodelling, biomarkers associated with LV remodelling and neurohumoral activation, and change in patient well-being assessed using a patient global assessment questionnaire. CONCLUSIONS: This trial will investigate the effect of neprilysin inhibition on LV remodelling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI.

Blood RNA Integrity is a Direct and Simple Reporter of Radiation Exposure and Prognosis: A Pilot Study.

In the event of a mass casualty radiation scenario, rapid assessment of patients' health and triage is required for optimal resource utilization. Identifying the level and extent of exposure as well as prioritization of care is extremely challenging under such disaster conditions. Blood-based biomarkers, such as RNA integrity numbers (RIN), could help healthcare personnel quickly and efficiently determine the extent and effect of multiple injuries on patients' health. Evaluation of the effect of different radiation doses, alone or in combination with burn injury, on total RNA integrity over multiple time points was performed. Total RNA integrity was tallied in blood samples for potential application as a marker of radiation exposure and survival. Groups of aged mice (3-6 mice/group, 13-18 months old) received 0.5, 1, 5, 10 or 20 Gy ionizing radiation. Two additional mouse groups received low-dose irradiation (0.5 or 1 Gy) with a 15% total body surface area (TBSA) burn injury. Animals were euthanized at 2 or 12 h and at day 1, 2, 3, 7 or 14 postirradiation, or when injury-mediated mortality occurred. Total RNA was isolated from blood. The quality of RNA was evaluated and RNA RIN were obtained. Analysis of RIN indicated that blood showed the clearest radiation effect. There was a time- and radiation-dose-dependent reduction in RIN that was first detectable at 12 h postirradiation for all doses in animals receiving irradiation alone. This effect was reversible in lower-dose groups (i.e., 0.5, 1 and 5 Gy) that survived to the end of the study (14 days). In contrast, the effect persisted for 10 and 20 Gy groups, which showed suppression of RIN values <4.5 with high mortalities. Radiation doses of 20 Gy were lethal and required euthanasia by day 6. A low RIN (<2.5) at any time point was associated with 100% mortality. Combined radiation-burn injury produced significantly increased mortality such that no dually-injured animals survived beyond day 3, and no radiation dose >1 Gy resulted in survival past day 1. More modest suppression of RIN was observed in the surviving dually challenged mice, and no statistically significant changes were identified in RIN values of burn-only mice at any time point. In this study of an animal model, a proof of concept is presented for a simple and accurate method of assessing radiation dose exposure in blood which potentially predicts lethality. RIN assessment of blood-derived RNA could form the basis for a clinical decision-support tool to guide healthcare providers under the strenuous conditions of a radiation-based mass casualty event.

A Semiautomated, Phenotypic, In Vitro Scratch Assay for Assessing Retinal Pigment Epithelial Cell Wound Healing.

Purpose: Age-related macular degeneration leads to retinal pigment epithelium (RPE) cell death and loss of central vision. In vivo studies have shown that the RPE layer has an innate, but limited, ability to repopulate atrophic areas. We aimed to establish a semiautomated, in vitro, wound healing assay workflow for targeted screening of compounds able to influence RPE wound healing. Methods: The ARPE-19 phenotype was evaluated using bright-field microscopy, immunocytochemistry, and quantitative real-time polymerase chain reaction. ARPE-19 monolayers were simultaneously scratched in a 96-well format and treated with Hoechst-33342 and an array of compounds. Initial wound dimensions and wound healing were subsequently evaluated using the EVOS FL Auto 2.0 imaging platform combined with automated image analyses. Results: Long-term cultured ARPE-19 cells displayed a more in vivo RPE-like phenotype compared with recently seeded or short-term cultured cells. No statistical difference of initial scratch width was observed between short-term and long-term cultured cells, but more wells were excluded from analyses in total in the latter case due to scratch width, scratch smoothness, and imaging errors. Furthermore, the previous time spent in continuous culture had an effect on the observation of an altered wound healing response to different treatment conditions. Conclusions: We have established a semiautomated, 96-well format, in vitro wound healing assay with a reproducible workflow. This would enable screening of a significant number of compounds and greatly advances the potential of identifying novel therapeutics that may enhance the innate ability of RPE cells to repopulate atrophic areas.

Increased Expression of Estrogen Receptor Beta in Idiopathic Progressive Subglottic Stenosis.

BACKGROUND/OBJECTIVES: Idiopathic progressive subglottic stenosis (IPSS) predominantly affects females in perimenopause. It has, therefore, been hypothesized that estrogen is involved in its pathogenesis. There are two main types of estrogen receptors: ER-α and ER-ß. Abnormal variants of ER-ß have previously been shown to be associated with poor wound healing. Estrogen receptors have recently been identified in subglottic tissue samples, with elevated levels of ER-α and progesterone receptors, and no expression of ER-ß, in stenotic specimens reported in one study. The objective of this study was to confirm the presence of estrogen receptors in the subglottis and investigate levels of expression and types of estrogen receptors in normal and stenotic subglottic tissue. METHODS: Subglottic tissue was obtained from three female and one male cadaver without laryngotracheal pathology to serve as controls. Subglottic tissue specimens from five female patients with IPSS were also analysed. Immunofluorescence stains for ER-α and ER-ß were performed on specimens. Staining patterns were compared qualitatively and semi-qualitatively between control and IPSS specimens. RESULTS: Immunofluorescence stains demonstrated the presence of both ER-α and ER-ß in subglottic tissue. IPSS specimens demonstrated significantly greater staining intensity of ER-α in the epithelium and ER-ß in glands and ducts compared to controls. CONCLUSIONS: This study confirms the presence of estrogen receptors in the subglottis. Increased expression of ER-α in the epithelium and ER-ß in glands and ducts in IPSS compared to controls may help to explain the predisposition to stenosis in these individuals. LEVEL OF EVIDENCE: 3b Laryngoscope, 130:2186-2191, 2020.

Hematologic malignancies of the larynx: A single institution review.

BACKGROUND: Primary hematologic malignancies of the larynx are rare diagnoses, accounting for less than 1% of all laryngeal tumors. They most commonly present as submucosal masses of the supraglottis, with symptoms including hoarseness, dysphagia, dyspnea and rarely cervical lymphadenopathy. PURPOSE: METHODS: Retrospective case series of patients in a tertiary academic laryngeal practice with hematologic malignancy of the larynx presenting over a 10 year period; charts were reviewed for diagnosis, symptoms, treatment, and outcomes. RESULTS: 12 patients were found to have primary presentation of a hematologic malignancy within the larynx between 2009 and 2019. A submucosal mass was the most common finding, and hoarseness was the most common symptom. Local control of disease was high. Airway obstruction was managed with tracheostomy. Several patients required tube feeding prior to disease control. Most patients underwent radiation therapy and chemotherapy, although surgery alone was effective in patients with isolated disease. CONCLUSIONS: Hematologic malignancies of the larynx are rare but treatable. Biopsy is the mainstay of diagnosis, and imaging may be helpful to exclude diseases with a similar physical presentation (i.e., laryngocele). Prognosis depends on diagnosis but is generally favorable.

Impact of a (poly)phenol-rich extract from the brown algae Ascophyllum nodosum on DNA damage and antioxidant activity in an overweight or obese population: a randomized controlled trial.

Background: Epidemiologic evidence suggests that a diet rich in (poly)phenols has beneficial effects on many chronic diseases. Brown seaweed is a rich source of (poly)phenols. Objective: The aim of this study was to investigate the bioavailability and effect of a brown seaweed (Ascophyllum nodosum) (poly)phenol extract on DNA damage, oxidative stress, and inflammation in vivo. Design: A randomized, double-blind, placebo-controlled crossover trial was conducted in 80 participants aged 30-65 y with a body mass index (in kg/m2) ≥25. The participants consumed either a 400-mg capsule containing 100 mg seaweed (poly)phenol and 300 mg maltodextrin or a 400-mg maltodextrin placebo control capsule daily for an 8-wk period. Bioactivity was assessed with a panel of blood-based markers including lymphocyte DNA damage, plasma oxidant capacity, C-reactive protein (CRP), and inflammatory cytokines. To explore the bioavailability of seaweed phenolics, an untargeted metabolomics analysis of urine and plasma samples after seaweed consumption was determined by ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Results: Consumption of the seaweed (poly)phenols resulted in a modest decrease in DNA damage but only in a subset of the total population who were obese. There were no significant changes in CRP, antioxidant status, or inflammatory cytokines. We identified phlorotannin metabolites that are considered potential biomarkers of seaweed consumption including pyrogallol/phloroglucinol-sulfate, hydroxytrifurahol A-glucuronide, dioxinodehydroeckol-glucuronide, diphlorethol sulfates, C-O-C dimer of phloroglucinol sulfate, and C-O-C dimer of phloroglucinol. Conclusions: To the best of our knowledge, this work represents the first comprehensive study investigating the bioactivity and bioavailability of seaweed (poly)phenolics in human participants. We identified several potential biomarkers of seaweed consumption. Intriguingly, the modest improvements in DNA damage were observed only in the obese subset of the total population. The subgroup analysis should be considered exploratory because it was not preplanned; therefore, it was not powered adequately. Elucidation of the biology underpinning this observation will require participant stratification according to weight in future studies. This trial was registered at clinicaltrials.gov as NCT02295878.

Assessment of Pliability and Elasticity of the External Nasal Skin in Patients With Unilateral Nasal Valve Collapse: A Static Biomechanical Evaluation.

IMPORTANCE: Understanding the skin biomechanics, specifically pliability and elasticity, in patients with nasal valve collapse may allow for new methods to assess which patients require more advanced nasal valve surgery. OBJECTIVE: To test the hypothesis that in patients with unilateral nasal valve collapse, the side of the nose with the collapse will have lower elasticity and increased pliability compared with the normal side, as assessed by a blinded observer using the Cutometer MPA 580. DESIGN, SETTING, AND PARTICIPANTS: Prospective, investigator-blinded, case-control cohort study of patients with unilateral nasal valve collapse and subjective nasal obstruction conducted in an academic otolaryngology-head and neck surgery clinic. INTERVENTIONS: Patients were assessed using the Cutometer MPA 580 by a blinded assessor. Three measurements were performed bilaterally on the exterior skin of the nose corresponding to the level of the inferior edge of the upper lateral cartilage. Measurements taken at the skin inferior to the zygoma were used as a control. MAIN OUTCOMES AND MEASURES: Primary outcome measures of the nasal skin were pliability (Uf, defined as the lengthening of the skin after 3 seconds of constant load) and elasticity (Ua/Uf, defined as the percentage of the skin that returned to its normal position 3 seconds after the release from the 3-second constant load). RESULTS: Of the 27 patients included in the study, 15 (56%) were male, and 12 (44%) were female; mean (SD) age, 44 (21) years (range, 16-90 years). There was no difference between the measurements of the skin overlying the area of nasal valve collapse in elasticity: side without collapse (0.960% [0.031%]) vs side with collapse (0.967% [0.036%]) (mean difference, 0.007%; 95% CI, -0.018% to 0.021%) (P = .90). However, there was a significant difference in pliability: side of the nose without collapse (0.520 [0.139] mm) vs side with collapse (0.610 [0.200]) (mean difference, 0.090 mm; 95% CI, 0.014-0.156 mm) (P = .02). CONCLUSIONS AND RELEVANCE: Although the skin in patients with nasal valve collapse appears to maintain its elasticity, it demonstrates an increased ability to stretch and lengthen compared with nasal skin of those without valve collapse. Future studies are required to determine whether the biomechanical changes are related to the length and severity of nasal obstruction, or whether these changes in the skin may help predict who will benefit from nasal valve surgery and whether these patients are at an increased risk of surgical failure. LEVEL OF EVIDENCE: 2.

A prospective cohort study assessing the clinical utility of the Cottle maneuver in nasal septal surgery.

BACKGROUND: A nasal septal deviation can have a significant detrimental effect on a patient's quality of life. Nasal valve collapse (NVC) often co-exists with a septal deviation. The Cottle maneuver is one of the most common methods to diagnose NVC; however, no study has assessed the efficacy of this physical exam finding. This study tests the hypothesis that patients with nasal obstruction due to a septal deviation with a negative pre-operative Cottle maneuver will demonstrate a greater improvement in their Nasal Obstruction Symptom Evaluation (NOSE) score, compared to patients who demonstrate a positive pre-operative Cottle maneuver, when assessed at 12 months following a septoplasty with turbinate diathermy. METHODS: This was a prospective Cohort Study. The population was 141 patients with nasal obstruction due to a septal deviation with or without nasal valve collapse, excluding patients with bilateral complete nasal valve collapse. Patients were placed in cohorts according to the results of the Cottle maneuver (positive or negative). A NOSE questionnaire was administered at baseline and 12-months after a septoplasty with turbinate diathermy. Non-adjusted NOSE scores were used (score out of 20). An ANOVA was used to compare if there was a difference in outcomes between patient cohorts. RESULTS: One hundred and forty-one patients completed 12-month follow-up with 71.5% of patients demonstrating a positive Cottle maneuver at baseline. The mean (95% C.I.) difference in NOSE score at 12 months between patients with a positive Cottle versus a negative Cottle was 0.18 (- 1.6 to 1.92; p = 0.38). CONCLUSION: In a univariate, single surgeon study, a positive Cottle Maneuver does not appear to influence outcomes in the described patient population compared to those with a negative Cottle Maneuver when undergoing a septoplasty.